T cells continuously recirculate to perform immune surveillance and effector functions. Within lymph nodes, naive T cells extravasate preferentially through high endothelial venules (HEVs) to survey dendritic cells for foreign antigens. If they fail to encounter cognate antigens, they recirculate to the blood via the efferent lymph. If they encounter cognate antigens, T cells undergo clonal expansion and changes in receptor expression that allow trafficking to first-barrier organs (e.g., skin or the gut mucosa), which they reach by crossing postcapillary venules (Masopust et al. (2013) Nat. Rev. Immunol., 13:309-320). Transendothelial migration involves multiple steps: selectin-mediated rolling, chemokine-triggered integrin activation and consequent firm adhesion, migration along the endothelial wall, and passage through the endothelial barrier (Ley et al. (2007) Nat. Rev. Immunol., 7:678-689). Each step is tightly regulated by membrane receptors on the T cell and the interacting endothelial cells. Chemokine receptors play a pivotal role, triggering rapid changes in T cell adhesion and cytoskeletal remodeling. Although crucial for adaptive immune responses to invading pathogens, T cell migration into peripheral tissues can also lead to inflammation and tissue destruction. For example, in patients receiving allogeneic bone marrow transplants, infiltration of donor T cells leads to graft-versus-host disease (GVHD), a life-threatening complication (Blazar et al. (2012) Nat. Rev. Immunol., 12:443-458). Thus, molecules that regulate T cell tissue infiltration are important therapeutic targets.
Graft versus host disease is a significant problem in patients receiving hematopoietic stem cell transplants, including patients with primary immunodeficiencies, Fanconi anemia, leukemia and lymphoma. This is particularly important for patients receiving allogeneic stem cells to fight leukemia, as these cells are by definition reactive to host tissues. GVHD is a major problem for allogeneic hematopoietic stem cell transplant, occurring with varying degree of severity in 30-70% of patients. Traditional approaches to prevention involve T cell depletion and immunosuppression. T cell depletion is achieved either by ex vivo manipulation of the donor graft (CD34+ selection or CD3+ depletion) or by administering T-cell depleting medications to the recipient (e.g., anti-thymocyte globulin, alemtuzumab). Currently, the combination of a calcineurin inhibitor (e.g., cyclosporine or tacrolimus) and methotrexate is the standard of care for GVHD prevention (Reshef, R. (2012) Clin. Adv. Hematol. Oncol., 10:663-5; Li et al. (2009) Immunotherapy 1:599-621).
The challenge for allogeneic stem cell transplantation is to reduce morbidity from GVHD while maintaining an efficient GVL response and supporting adequate recovery of the immune system. The problem with current strategies is that they affect both GVHD and GVL. Although T cell depletion can be effective in decreasing the rate of GVHD in some subjects, patients have a higher risk for disease relapse due to loss of the GVL response, which is also mediated at least in part by T cells. Thus, this strategy is not suitable for many patients. Similar concerns apply to treatment with immunosuppressive agents, and for many if not all of the novel approaches under development.